Piperazine derivatives



United States Patent 3,277,094 PIPERAZINE DERIVATIVES V 7 Lincoln Harvey Werner, Summit, NJ., assignor to CIBA Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May 10, 1965, Ser. No. 454,703 22 Claims. (Cl. 260-268) This is a continuation-in-part of my application Serial No. 395,007, filed September 8, 1964, which in turn is a continuation-in-part of my application Serial No. 376,572, filed June 19, 1964, now abandoned, which in turn is a continuation-in-part of my application Serial -No. 317,130, filed October 18, 1963 (now abandoned).

The present invention concerns and has for its object the provision of acylated aryl ethers and methods for their preparation.

More particularly the invention relates to N-(acyl phenyl-X-lower alkyl)- N-monocyclic aryl-diaza-cycloalkanes, especially to those of the formula:

in which Ac stands for the acyl radical of an organic carlboxylic acid, Ph for a phenylene radical, X for an oxygen or sulfur atom, Alk for lower alkylene separating X from the nitrogen atom by at least two carbon atoms, each of Alk and Alk for lower alkylene separating the two nitrogen atoms by two to three carbon atoms, and Ar for a monocyclic aryl group, carbonyl derivatives, N-oxides, quaternary ammonium derivatives and salts of these compounds.

The acyl group Ac is primarily the radical of an aliphatic carboxylic acid, particularly lower alkanoyl, especially acetyl, as wvell as formyl, propionyl or n-butyryl, but also lower alkenoyl, e.g. acrylyl, or the acyl radical of a substituted aliphatic carboxylic acid, for example, of a carbocyclic aryl-aliphatic carboxylic acid, such as phenyllower alkanoyl or alkenoyl e.g. phenylacetyl, 3-phenylpropionyl or cinnamoyl, or substituted phenyl-lower alkanoyl or alkenoyl such as (lower alkyl)-phenyl-lower alkanoyl or alkenoyl, e.g. Pmethyl-phenylacetyl or 4- methyl-cinnamoyl, (lower alkoxy)-phenyl-lower alkanoyl or alkenoyl, e.g. 4-methoxy-phenylacetyl, 3,4,5-trimethoxyphenylacetyl, 4-methoxy-cinnamoyl or 3,4,5-trimethoxycinnamoyl, (halogeno) -phenyl-lower alkanoyl or alkenoyl, e.g. 4-chloro-phenylacetyl, 3-(4-fluoro-phenyl)-propionyl, 4-fluoro-cinnamoyl or 4-chloro-cinnamoyl as well as the radical of a heterocyclic aryl-aliphatic carboxylic acid, such as pyridyl-lower alkanoyl or alkenoyl, e.g. 2-pyridyl acetyl, 3-(3-pyridyl)-propionyl or 3-(3-pyridyl)-acrylyl.

Other acyl radicals Ac are those of aromatic carboxylic acids, especially those of monocyclic carbocyclic aryl carboxylic acids, for example benzoyl or substituted benzoyl, such as (lower aIkyD-benzoyl, e.g. 4-methyl-benzoyl, (lower alkoxy)-benzoyl, e.g. 4-methoxy-benzoyl, or (halogeno)-benzoyl, e.g. 4-fluoro-benzoyl or 4-chloro-benzoyl, as well as the acyl radicals of monocyclic heterocyclic aryl carboxylic acids, for example a pyridoyl or substituted pyridoyl radical, such as nicotinoyl, isonicotinoyl or (lower alkyl)-pyridoyl, e.g. Z-methyl-isonicotinoyl. One or more than one of the same or of different acyl radicals may be substituting any of the positions available for substitution in the phenylene radical Ph. 7

Apart from acyl, the phenylene radical Ph may contain one or more than one of the same or of difl'erent additional substituents attached to any of the positions available for substitution. Such additional substituents are particularly etherified hydroxy, especially lower alkoxy, e.g. methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy, as well as lower alkyl, having preferably from one to four carbon Patented Oct. 4, 1966 atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary butyl, esterified hydroxy, particularly halogeno having preferably an atomic weight between 19 and both included, such as fluoro, chloro or bromo.

The group X is above all an oxygen atom but may also be a sulfur atom.

The lower alkylene portion Alk has preferably from two to seven carbon atoms and separates X from the nitrogen atom by two to seven carbon atoms. It is, for example, represented by unbranched lower alkylene, i.e. 1,2- ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6- hexylene or 1,7-heptylene but may also be represented by branched lower alkylene, e.g. 1,2- or 2,3-propylene, 1,3- or 2,4-butylene, 1,3-, 1,4- or 2,4-pentylene, 1,5-hexylene, 1,5- or 2,6-heptylene.

Each of the lower alkylene groups Alk and Alk has preferably also from two to seven, more especially two to three, carbon atoms, and separates the two nitrogen atoms by two to three carbon atoms. These alkylene radicals are, above all, represented by 1,2-ethylene, as well as by 1,2- or 1,3-propylene, but also by LL or 2,3-butylene, 1,2-isobutylene, 1,2- or 2,3-pentylene, 1,2-isopentylene or 3-methyl-1,2-isopentylene, 1,2- or 3,4-hexylene or 1,2-heptylene.

The monocyclic aryl group Ar stands primarily for monocyclic carbocyclic aryl i.e. phenyl or substituted phenyl having one or more than one of the same or of different substituents attached to any of the positions available for substitution. Such substituents are particularly lower alkyl, e.g. methyl, ethyl, n-propyl or isopropyl, etherified hydroxy or mercapto, especially lower alkoxy or lower alkylmercapto, e.g. methoxy, ethoxy, npropoxy or isopropoxy; methylor ethylmercapto, esterified hydroxy, especially halogeno, e.g. fluoro, chloro or bromo.

A monocyclic aryl group Ar stands also for monocyclic heterocyclic aryl, especially monocyclic azacyclic aryl, particularly pyridyl, e.g. 2-, 3- or 4-pyridyl, as well as for monocyclic oxacyclic or thiacyclic aryl, such as furyl, e.g. Z-furyl, or thienyl, e.g. Z-thienyl.

The compounds of this invention may also be in the form of carbonyl derivatives, which are preferably those containing at least one nitrogen atom, such as imines, especially aliphatic imines in which the aliphatic radical stands above all for lower alkyl, but also for cycloalkyl or cycloalkyl-lower alkyl having from three to eight, especially from five to seven, ring carbon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylethyl, 1 or 2-cyclohexylethyl, or cycloheptylmethyl; oximes, O-lower alkyloximes, hydrazones, monoor di-lower alkylliydrazones, or semicarbazones; the lower alkyl group therein contains up to seven carbon atoms and has been exemplified under the phenylene radical Ph.

N-oxides are especially in the form of acid addition salts, such as those of pharmaceutically acceptable acids.

Quaternary ammonium derivatives are those with reactive esters formed by alcohols and strong acids, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide, phenyllower alkyl halides, e.g. benzyl chloride, benzyl bromide or 2-phenylethyl bromide, di-lower alkyl sulfates, e.g. dimethyl or diethyl sulfate, lower alkyl lower alkane sufonates, e.g. methyl or ethyl methane or ethane sulfonate, or lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides. Monoor poly-quaternary ammonium compounds may be formed, depending on the conditions of the quaternization reaction.

The compounds of this invention exhibit valuable pharmacological properties. For example, they show an Outstanding antihypertensive activity and are, therefore, useful in the treatment of hypertensive conditions, such as essential hypertension and the like. The compounds are orally active, their antihypertcnsive eflects are of prolonged duration and are accompanied by little or no side effects, e.g. tachycardia and the like.

In pharmacological tests with dogs, ithas been shown that they block the pressor effects of epinephrine and norepinephrine, as well as the pressor effects caused by carotid occlusion.

It has also been found that the compounds of this in vention increase, blood flow, particularly the peripheral blood flow, as well as the renal blood flow; they are, therefore, also useful in the treatment of peripheral vascular diseases, e.g. Reynauds disease and the like.

The compounds of this invention also have antifibrillatory and antiarrhythmic effects, and are useful in the treatment of heart fibrillations and arrhythmias of neurogenic or cardiogenic, auricular or ventricular nature. The antifibrillatory properties exhibited by the compounds of this invention are of prolonged nature.

Furthermore, compounds of this invention also show antihistaminic properties and are, therefore, useful as antihistaminic agents in the treatment of allergic disorders and the like.

Compounds of this invention also exhibit anti-inflammatory effects, and are, therefore, useful as anti-inflammatory agents, for example, in place of corticoid steroids, e.g. cortisone, hydrocortisone and the like, in the treatment of tissue inflammations, such as arthritic inflammations and similar conditions.

Especially useful are the compounds of the formula in which Ac is lower alkanoyl, especially acetyl, R R and R have the previously-given meaning, R primarily is lower alkoxy and R hydrogen, the letter mi has the previously-given meaning, but stands, above all, for one of the integers from 2 to 4, lower alkylimines thereof and pharmaceutically acceptable acid addition salts of these compounds.

The compounds of this invention are prepared according to known methods. For example, they are obtained by (a) reacting an N-monocyclic aryl-diaza-cycloalkane, especially that of the formula with a reactive ester of an acyl-phenyl-X-lower alkanol, particularly such derived from the alcohol having the formula 4 or (b) reacting an acyl-phenyl-X-lower alkylamine, especially that of the formula Ac-PhXAlk NH with a reactive diester of an N,N-bis-(hydroxy-lower alkyl)-N-monocyclic arylamine, particularly such derived from the compound having the formula or (c) reacting a monocyclic arylamine, especially that of the formula H NAr /Alk2 Ac-Ph-X-Alln-NH NH-Ari with a reactive diester of a lower alkylenediol, particularly such derived from the diol of the formula and if desired, converting the acyl group in a resulting;

compound into another acyl group, and/or converting a resulting compound into a ketone derivative and/or an N-oxide or a quaternary ammonium compound thereof and/ or converting a resulting basic compound into a salt thereof and/ or converting a resulting salt into the basic compound or into another salt and/or separating a resulting mixture of isomers into'the single isomers.

Reaction (a) may also be carried out with a metal salt of an N-monocyclic aryl-diaza-cycloalkane, such as an alkali metal, e.g., lithium, sodium or potassium salt. It

is prepared according to known, methods; for example, a

solution of the N-monocyclic aryl-diaza-cycloalkane in a suitable solvent or solvent mixture, the selection of which depends on the solubility of the starting material and the reactivity of the salt-forming reagent, is treated with an alkali metal, e.g. sodium, or with an alkali metal hydride or amide, e.g. lithium, sodium or potassium hydride or. amide, with an alkali metal carbonate, e.g. sodium or poi tassium carbonate, or an alkali metal lower alkoxide, if

necessary, while cooling or heating, and/or in the atmosphere of an inert gas, e.g. nitrogen. A metal salt-forming reagent may also be added to a mixture of the two reactants, preferably a solution thereof, thus forming the salt in situ and bringing about the desired reaction.

A reactive ester of an acyl-phenyl-X-lower alkanol is.

primarily an ester thereof with a strong inorganic acid, particularly a hydrohalic acid, e.g. hydrochloric or hydrobromic acid, as well as sulfuric acid, or a strong organic sulfonic acid, e.g. methane or p-toluene sulfonic acid.

The preferred starting materials are represented by the I acyl-phenyl-X-lower alkyl halides, in which lower alkyl separates the group X from halogeno by at least two car- I bon atoms, and halogeno stands or bromo.

Reaction (a) is carried out according to known methods.

particularly for chloro tralized by adding an excess of this starting material, or

any other base, such as the salt-forming reagent, e.g.

sodium or potassium carbonate. The reaction is preferably performed in the presence of a diluent, for example an ether, e.g. tetrahydrofuran, p-dioxane or diethyleneglycol dimethylether, a formarnide, e.g. dimethylform;

Thus, whenever the free N-monocyclic aryl-diaza-1 cycloalkane is used, the generated acid is preferably neu-,

amide, a hydrocarbon, e.g. benzene, or an alcohol, e.g. ethanol, if necessary, while cooling or preferably at an elevated temperature, in an open or closed vessel and/ or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials used in the above reaction are known or if new, may be prepared according to known methods. Thus, a phenol or thiophenol compound is acylated by treatment with an organic carboxylic acid halide, particularly the chloride, in the presence of a Friedel-Crafts reagent, e.g. aluminum chloride, and the acylated phenol or thiophenol, or preferably a salt, particularly an alkali metal salt, thereof is then reacted with a reactive ester of a halogeno-lower alkanol, in which halogeno is separated from reactive esterified hydroxy by at least two carbon atoms, for example, with a correspond ing lower alkylene halide, in which the two halogens are of the same or of different atomic weights.

The reactive diester used in reaction (b) is primarily that of a hydrohalic acid having preferably a molecular weight between 36 and 81 both inclusive, i.e. that of hydrochloric or hydrobromic acid, as well as that of an organic sulfonic acid. The reaction is carried out according to known conditions, such as described before, if necessary, at an elevated temperature, in a closed vessel, in the atmosphere of an inert gas, e.g. nitrogen, and/or in the presence of an acid neutralizing base.

The starting materials used in the above reaction are prepared according to known methods; for example, the previously-described reactive ester of an acyl-phenyl-X- lower alkanol, when treated with ammonia or with another reagent capable of converting a reactive esterified hydroxyl group into amino, such as an alkali metal salt of phtha-limide, followed by hydrazine, may be converted into the desired starting material.

Reaction (c) is also carried out according to known methods, such as those mentioned hereinbefore. The reactive diester of an N,N-bis-(hydroXy-lower alkyl)-N- (acyl-phenyl-X)-lower alkylamine, is obtained, for example, by treating a reactive ester of a corresponding acylphenyl-X-lower alkanol, with an N,N-di-(hydroxy-lower alkyl)-amine, and converting in the resulting N,N-bis- (hydroxy -lower alkyl) -N-(acyl-phenyl-X)-lower alkylamine the free hydroxyl groups into reactive esterified hydroxyl groups, such as halogeno, e.g. chloro or bromo, for example, by treatment with a thionyl halide, e.g, thionyl chloride, or a phosphorus halide, e.g. phosphorus tribromide, or into organic sulfonyloxy groups, e.g. methylsulfonyloxy or p-toluene-sulfonyloxy, for example, by treatment with an organic sulfonic acid halide, e.g. methane or p-toluene sulfonyl chloride.

Reaction (d) also is carried out according to known methods, such as the previously shown procedures. The starting materials are prepared according to any of the known methods useful for the preparation of asymmetrically N,N'-disubstituted alkylenediamines.

In a resulting compound, an acyl group may be converted into another acyl group, for example, by treatment of a resulting compound having a lower alkanoyl substituent, particularly acetyl, with an aldehyde, such as an aliphatic aldehyde, e.g. a lower alkanal, or a carbocyclic aryl carboxaldehyde, e.g. benzaldehyde, a carbocyclic aryl-aliphatic aldehyde, e.g phenylacetaldehyde, or a heterocyclic aryl carboxaldehyde, e.g. nicotinaldehyde, in the presence of a suitable base. Acyl radicals of unsaturated organic carboxylic acids, such as lower alkenoyl, phenyllower alkenoyl or pyridyl-lower alkenoyl radicals, may be converted into the acyl radicals of the corresponding saturated organic carboxylic acids by reduction, for example that carried out with catalytically activated hydrogen.

The free keto-compounds of the invention can be converted into carbonyl derivatives, especially into nitrogencontaining carbonyl derivatives, according to methods known per se. Thus, for example, a compound obtained containing a free keto group attached to the phenylene radical Ph, can be reacted with compounds containing a primary amino group, such as primary amines, especially primary lower alkyl amines, e.g. methylamine, ethylamine, propylamine, isopropylamine, or n-butylamine, in order to form imines; with hydroxylamine to form oximes, which latter may be etherified, for example with lower alkyl halides, to form O-lower alkyloximes; with hydrazine or asymmetrical substituted hydrazines, especially lower alkyl hydrazines or N,N-di-lower alkylhydrazines, to form hydrazones; or with semicarbazide to form semicarbazones.

N-oxides of the invention can also be prepared according to known methods. For example, a resulting free compound, preferably a solution thereof in an inert solvent, can be reacted with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfun'c acid, or an organic peracid, such as an organic percarboxylic acid, e.g. peracetic, perbenzoic or rnOnoper-phthalic acid, or an organic persulfonic acid, to form the corresponding N-oxide. A resulting N-oxide may be converted into an acid addition salt thereof according to the method described below.

Quaternary ammonium derivatives of this invention are obtained according to known methods, for example, by reacting the free compound with an ester of an alcohol and a strong inorganic or organic acid, such as one of those previously mentioned. The quaternizing reaction may be performed in the presence or absence of a solvent, if necessary, while cooling or at an elevated temperature, in a closed vessel, and/ or in the atmosphere of an inert gas, e.g. nitrogen.

Resulting quaternary ammonium compounds may be converted into other quaternary ammonium compounds, such as the corresponding quaternary ammonium hydroxides, according to known methods. The latter, for example, are obtained by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium salt with an anion exchange preparation or by electrodialysis. From a resulting quaternary ammonium hydroxide, there can be prepared a quaternary ammonium salt by reaction with an acid or with a lower alkyl sulfate, e.g. methyl or ethyl sulfate. A quaternary ammonium salt is also converted directly into another quaternary ammonium salt without the formation of an intermediary quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or with hydrogen chloride in anhydrous methanol, to yield the quaternary ammonium chloride, or a quaternary ammonium salt may be treated with an anion exchange preparation and thus be converted into another quaternary ammonium salt. Quaternary ammonium compounds may be isolated in the form of hydrates or may contain solvent of crystallization.

A resulting basic compound can be converted into its acid addition salt according to known methods, such as reacting it with an acid, such as one of the inorganic or organic acids mentioned below, for example, by treating a solution of the base in a solvent or solvent mixture with.

the acid or a solution thereof, or with an anion exchange preparation, and isolating the desired salt. The monoor poly-salts may also be obtained in the form of hydrates thereof or may contain solvent of crystallization.

A resulting acid addition salt may be converted into the free compound according to known methods, for example, by treatment with a base, such as a metal hydroxide, e.g. lithium, sodium, potassium or calcium hydroxide, a metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, ammonia, or with a hydroxyl ion exchange preparation.

A resulting acid addition salt may be converted into another salt according to known methods, for example, by treatment of a salt with an anion exchange preparation. Furthermore, a salt with an inorganic acid may be treated with a metal, e.g. sodium, barium or silver salt of an acid in the presence of an appropriate solvent, for example, a solvent, in which a resulting inorganic compound in insoluble and is thus removed from the reaction medium, to yield another acid addition salt.

A resulting mixture of isomers may be separated into single isomers. For example, a mixture of diastereoisomeric compounds may be separated into the individual racemic compounds on the basis of physico-chemical differences, such as solubility, for example, by fractional crystallization. Racemates may be resolved into the optically active dand l-forms according to known resolution procedures, for example, reacting the free compound, preferably a solution thereof, with one of the optically active forms of an acid having an asymmetric carbon atom or a solution thereof. The resulting mixture of acid addition salts is then separated into the single acid addition salts of optically activecompounds on the basis of physico-chernical dilferencespeg. solubility, and the free and optically active base is liberated from the resulting salt according to the previously-described procedure, and may be converted into another acid addition salt, an N-oxide, an acid addition salt of an N-oxide or a quaternary ammonium compound aocording to the above-described methods. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free compound is referred to in this context, a corresponding salt, especially a pharmaceutically acceptable salt, is also intended, provided such is possible or appropriate under the circumstances.

Salts of the free compounds of this invention are acid addition salts, preferably such that are pharmaceutically acceptable, derived for example, of inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid or organic acids, such as organic carboxylic aids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, glucuronic, benzoic, salicylic, 4-amino-salicylic, 2-acetoxybenzoic, pamoic, nicotinic or isonicotinic acid, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, 2-hydroxy ethane sulfonic, ethane 1,2-disu-lfonic, benzene sulfonic, toluene sulfonic or naphthalene 2-sulfonic acid. Acid addition salts also may serve as intermediates for the preparation of other salts, such as the pharmaceutically acceptable, non-toxic acid addition salts, or in the purification of the free compounds, as well as for identification and characterization purposes. Acid addition salts primarily used for the latter purpose are, for example, those with certain inorganic acids, e.g. perchloric phosphotungstic, phosphomolybdic, chloroplatinic or Reinecke acid or those with acidic organic nitro compounds, e.g. picric, picrolonic or flavianic acid.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as [the starting material and the remaining step(s) of the process is (are) carried out or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions or in which the reaction components are used in the form of their salts, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The new compounds of this invention are useful in the form of compositions for enteral, e.g. oral, or parenteral stearyl alcohol, talc, gums, acacia, tragacanth, polyalkylene glycols, propylene glycol, water and the like.

vary widely and depend inter alia upon the desired physical appearance or size of the composition or method of manufacture. Encapsulation may be eflected using, if desired, the same excipients as those used for tablets. If necessary, the compositions having as the effective pharmacological ingredient one of the compounds of this invention, may contain other auxiliary substances, such as preserving, stabilizing, wetting, emulsifying, coloring or flavoring agents, salts for varying the osmotic pressure, or buffers. They may also contain, in combination, other 1 The compounding of the formulations is generally carried out in the manner therapeutically useful substances.

normally employed in the art, i.e. by manufacturing a mixture or a granulate. Any compatible color, approved and certified under the provisions of the Federal Food,

Drug and Cosmetic Law may be used for aesthetic purt poses or as a means of identification.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.

Example 1 A mixture of 5.0 g. of 4-(4-bromo-butyloxy)-3-rnethoxy-acetophenone in 25 m1. of ethanol and 5.4 g. of 1- phenyl-piperazine is refluxed for twenty-four hours.

After cooling, the resulting solution is filtered and concentrated under reduced pressure. The residue is partitioned between water and diethyl ether.- The organic phase is washed twice with water, dried and concentrated to yield 6.4 g. of 1-[4-(4-acetyl-Lmethoxy-phenyloxy)- butyl]-4-phenyl-piperazine of the formula which is dissolved in ethyl acetate. solution of anhydrous hydrogen chloride in ethyl acetate, the 1- [4- (4-acetyl-2-methoxy-phenyloxy) -butyl] -4-phenylpiperazine dihydrochloride precipitates and is recrystallized from ethanol, M.P. 205 (dec.).

The starting material is prepared as follows: To a solution of 8.0 g. of sodium hydroxide in ml. of ethanol,

prepared at an elevated temperature, is added 33.2 g. of

4-acetyl-Z-methoxy-phenol in ml. of ethanol. The

sodium salt of the 4-acetyl-2-methoxy-phenol precipitates immediately, and a solution of 86.4 g. of 1,4-dibromobutane in 90 ml. of ethanol is added. The reaction mix-v butyloxy)-3-methoxy-acetophenone is collected at 168- 172/l mm.; yield: 15.7 g.

Example 2 A mixture of 5.2 g. of 4-(4-bromo-butyloxy)-3-methoxy-acetophenone and 6.1 g. of 1-(3-methyl)-piperazine in 25 ml. of ethanol is reacted as described in Example 1 to yield 4.9 g. of 1-[4-(4-acetyl-2-methoxy-phenyloxy)- The quantity and the nature of the carrier ingredients may.

On addition of a t 9 10 butyl]-4-(3-methylphenyl)-piperazine dihydrochloride of Example 3 to yield the 4-[2-(4-acetyl-2-methoxy-phenylthe formula oxy)-etl1yl]-4-(3-methyl-phenyl plperazlne of the formula CHPGH: H3oc o-orncm-cHl-orn-N /N' .2Hc1

i CHz-CH:

CH3 H3 which melts at 188l91 (with decomposition) after two CHPCH2 recrystallizations from isopropanol.

Example 3 g cnz-orn on H A mixture of 4.6 g. of 4-(Z-chloro-ethyloxy)-3-methoxyl acetophenone and 6.5 g. of l-phenyl-piperazine in 25 m1. whlch 1s converted into its dlhYtil'OChlOI'ldG, melting at of ethanol is refluxed for twenty-four hours. After 0001- 182-l86 after two recrystallizations from lsopropanol. ing and standing at room temperature, 2.85 g. of l-phenylh d hl d t 11' d filtered off Example 6 1 erazme roc on e crys a izes an is p h filtrate is concentrated under reduced pressure and A mlxture of y y) 3- the residue is partitioned between diethyl ether and water. 10 acetophellone 25 9 ethanol and of '0 The organic phase is separated, washed twice with water, p y )-p p 1S refluxed for ydried and concentrated. The residue, weighing 7.5 g. hours f f coll'cflltratfid under {educed Pressureand containing the l-[2-(4-acetyl-Z-methoxy-phenyloxy)- The residue is partitioned between diethyl ether and ethyl] 4 phenyl piperazine f the f ula water, and the organic phase 1s separated, dried and evap- 15 orated under reduced pressure. The resldue is dissolved OHFOH? in ethyl acetate, and the 1-[2-(4-acetyl-2-methoxy-phenyloxy)-ethyl]-4 (2-chloro-phenyl)-piperazine hydrochlofi ride of the formula O C zC 2 1130-0 OCHzCHzN /N@ .1101 is dissolved in ethyl acetate and treated with a concenl J; trated solution of anhydrous hydrogen chloride in ethyl 3 1 acetate- The y y-P Y y)- precipitates by adding a saturated solution of hydrogen yl]-4-phenyl-piperazine dihydrochloride precipitates, is filchloride in ethyl acetate. It is filtered off and partitioned tered E a is r y lliz from ethanol, between water and chloroform. The organic solution is (with decomposition). separated and concentrated; the residue is treated with The Starting material used in the above Procedure is acetone to yield the crystalline hydrochloride salt, which P p as follows: Y Using 0f Y melts at 173-175 after recrystallization from isopromethoxyphenol in 120 ml. of ethanol, 8.0 g. of sodium 1,

hydroxide in 100 ml. of ethanol and 43 g. of 2-chloro- Example 7 ethyl :bromide in ml. of ethanol and carrying out the A solution of 6.3 g. of 4-(5-bromo pentyloxy)-3-methreaction as descrlbed in Example 1 but omitting the oxy-acetophenone and 6.5 g. of l-phenyl-plperazine in 20 dlstll'latlgn g g z g gi gg g iz232%. ml. of ethanol is refluxed for 24 hours. The reaction mixgg p ig gz from mixture of ethanol and ture is cooled to room temperature, filtered and concenf l 1 trated under reduced pressure. The residue is dissolved Pe oeume in diethyl ether, the organic solution is washed with water, dried and concentrated under reduced pressure. A mixture of 5.6 g. of 4-(2-chloro-ethyloxy)-3-meth- The resulting 1-[5-(4 acety1 2-methoxy-phenyloxy)- Example 4 oxy-acetophenone and 8.6 g. of I-(Z-methyl-phenyD-pi- 40 pentyl]-4-phenyl-piperazine of the formula CHCH3 H3Cfi OCHz-CH2CH3-CH3CH7N /N o CH CH OOH;

perazine in 25 ml. of ethanol is refluxed for twenty-four is dissolved in ethyl acetate and treated with a saturated hours and worked up as described in Example 3. The solution of hydrogen chloride in ethyl acetate. The resulting 4-[2-(4-acetyl 2-methoxy-phenyloxy)-ethyl]-1- resulting 1-[5-(4-acetyl-Z-methoxy-phenyloxy)-pentyl]-4- (Z-methyl-phenyl)-piperazine of the formula phenyl-piperazine dihydrochloride is filtered oil and recrystallized twice from ethanol, M.P. 185 (with decom- CHPCHQ position); yield; 6.3 g.

HSCA; CH2 CH2 N/ x The starting material used in the above procedure is I; prepared as follows: To a solution of 5.32 g. of sodium 00113 Ha hydroxide in ml. of ethanol is added a solution of 22.0 g. of 4-acetyl 2-methoxy-phenol in 80 ml. of ethanol,

is converted into its dihydrochloride, which melts at 200- and then a solution of 45.9 gof 1,5-dibI0m0-PeI1taHe in 203 (with decomposition). 70 50 ml. of ethanol. The reaction mixture is refluxed for sixteen hours, and, after standing at room temperature Example 5 for several hours, it is filtered, and the filtrate is concen- A mixture of 5.6 g. of 4-(2-chloro-ethyloxy)-3-methtrated under reduced presure. The residue is taken up oxy-acetophenone and 8.5 g. of 1-(3-methyl-phenyl)- in chloroform; the solid material is filtered ofl and the piperazine in 25 ml. of ethanol is reacted as described in filtrate is Washed with a l N aqueous solution of sodium hydroxide. After drying, the organic solution is concentrated, and the resulting 4-(5-bromo-pentyloxy) 3-methoxy-acetophenone is purified by distillation and collected at l98202/1.5 mm.; yield: 150.0 g.; it solidifies on standing M.P. 54-60".

Example 8 A mixture of 6.6 g. of 4-(6=bromohexyloxy)-3-methoxy-acetophenone and 6.5 g. of l-phenyl-piperazine in 33 ml. of ethanol is reacted as described in Example 7. The resulting 1 [6 (4 acetyl 2 methoxy phenyloxy)- hexyl]-4-phenyl-piperazine of the formula OCH; is converted into its dihydrochloride, which melts at 175- 178 (with decomposition) after two recrystallizations from ethanol; yield: 7.7 g.

The starting material used in the above procedure is prepared by adding to a solution of 12.0 g. of sodium hydroxide in 150 m1. of ethanol, 49.9 g. of 4-acetyl-2- methoxy-phenol in 180 ml. of ethanol and reacting the resulting mixture with 109.8 g. of 1,6-dibromohexane in 100 ml. of ethanol according to the procedure described in Example 7; the resulting 4-(6-bromohexyloxy)-3-methoxy-acetophenone is purified by distillation and collected at l92/0.05 mm.; yield: 31.7 g.

Example 9 which is converted into its dihydrochloride, M.P. 160 (with decomposition) after four recrystallizations from isopropanol; yield: 2.8 g.

The above 1 [4 (4 cinnamoyl 2 methoxyphenyloxy) -butyl]-4-phenyl-piperazine, when treated with catalytically activated hydrogen, yields the 1-{4-[2-methoxy 4 (3 phenyl propionyl) phenyloxy] butyl}- 4-phenyl-piperazine. The starting material used in the above procedure is prepared as follows: To a solution of 0.94 g. of sodium hydroxide in 10 ml. of water is added a solution of 5.4 g. of 4-(4-bromobutyloxy)-3-methoxyacetophenone in ml. of ethanol. While stirring, 1.9 g. of benzaldehyde is added; stirring at room temperature is then continued for one hour. The desired product separates as an oil, which is isolated by decanting the supernatant liquid, treated with Water and dissolved in diethyl ether. The organic solution is dried and evaporated to yield 6.0 g. of the oily (4-(4-bromo-butyloxy)3-methoxybenzalacetophenone, which solidifies after standing for several days, but is used without further purification.

The following compounds are prepared according to the previously described procedure:

1 {4 [4 (4 chloro-cinnamoyl) 2 methoxyphenyloxy] butyl} 4 phenyl piperazine, the dihydrochloride of which melts at 198 (with decomposition), and which is prepared by reacting 4-(4-bromo-butyloxy)- 3-methoxy-(4-chloro-benzal)-acetophenone, M.P. 95-97", and l-phenyl-piperazine;

4 phenyl 1 {2 methoxy 4 [4 (3,4,5-trimethoxycinnamoyl) phenyloxy] butyl} piperazine, the dihydrochloride of which melts at 153 (with decomposition),

and which is prepared by reacting 4-(4bromo-butyloxy)- 3 methoxy (3,4,5 trimethoxy benzal) acetophenone, M.P. 107-109, with l-phenyl-piperazine; and

1 [2 (4 cinnamoyl 2 methoxy phenyloxy)- ethyl]-4-phenyl-piperazine, the dihydrochloride of which melts at 246 (with decomposition), and which is prepared by reacting 4-(2 chloro ethyloxy) 3 methoxybenzalacetophenone, M.P. 1l0-ll2, with l-phenyl-piperazine.

Example 10 A solution of 5.4 g. of 3-(4-bromo-butyloxy)-acetophenone and 5.5 g. of l-phenyl-piperazine in 30 ml. of ethanol is refluxed for 24 hours and is then worked up as described in Example 7 to yield the l-[4-(3-acetyl- CH=CH CHz-CH;

phenyloxy) butyl] 4 phenyl piperazine of the formula which is converted into its dihydrochloride, M.P. 185 (with decomposition); yield: 4.9 g.

The starting material used in the above procedure is CHrCH;

CHr-CH:

prepared 'by reacting 18.1 g. of 2-hydroxy-acetophenone in: 100 ml. of ethanol with 5.3 g. of sodium hydroxide in.

70 ml. of ethanol and then with 43.0 g. of 1,4-di-bromobutane in ml. of ethanol according to the procedure described in Example 7; the desired 3-(4-bromo-butyloxy)- acetophenone is purified by distillation and collected at 152-l56/l.0 mm.; yield: 14.0 g.

Other compounds, which are prepared according to the above procedure, are, for example,

1 [4 (2 acetyl phenyloxy) butyl] 4 phenyl- CH3--CH1 CHr-CH:

the dihydrochloride of which melts at 201205 (with decomposition), and which is prepared by reacting the.

4-(4-bromo-butyloxy)-acetophenone with l-phenyl-piperazine (the starting material is prepared as follows: A

mixture of 27.3 g. of 4-hydroxy-acetophenone in ml. of N,N-dimethylformamide and 9.4 g. of a 53 percent suspension of sodium hydride in mineral oil is stirred.

and then treated with 80.0 g. of 1,4-dibromobutane. The

' temperature is kept between 45 and 50 for sixteen hours and after cooling, the solid material is filtered oil and the filtrate is evaporated under reduced pressure. The residue is partitioned between diethyl ether and water; the organic phase is washed with water, dried and concentrated to yield the 4-(4-bromo-butyloxy)-acetophenone, which is distilled and collected at l60l70/l.0

composition), and which is prepared by reacting 4(2-- chloroethyloxy)-acetophenone, B.P. l40/0.7 mm. with I l-phenyl-piperazine;

1- [2- (4-benzoyl-phenyloxy) -ethyl] -4-phenyl-piperazine, the dihydrochloride of which melts at l96-l98 (with decomposition), and which is prepared by reacting 4-(2- chloro-ethyloxy)-benzophenone with phenyl-piperazine (the startmg materral is prepared by reacting 19.8 g. of

4-hydroxy-benzophenone in ml. of N,N-dimethylformamrde with 4.5 g. of 53 percent suspension of sodium hydride in mineral oil and then with 22.0 g. of l-bromo- 2-chloroethane according to the above described procedure; the 4-(2-chloro-ethylox'y)-benzophenone melts at 73" yield: 6.0 g.); and

4-phenyl-l- [4-(4-phenylacetyl-phenyloxy -butyl] -piperazine, the dihydrochloride of which melts at 188 (with decomposition), and which is prepared by reacting benzyl 4-(4-brom0-butyloxy)-pheny1 ketone, M.P. 87-91, with l-phenyl-piperazine.

Example 11 A mixture of 5.7 g. of 4-(4bromo-butyloxy)-2-methylacetophenone and 6.5 g. of l-phenyl-piperazine in 30 ml. of ethanol is refluxed for 24 hours and worked up as described in Example 7 to yield 1-[4-(4-acetyl-3-methylphenyloxy)-butyl]-4-phenyl-piperazine of the formula yield 16.5 of 4-(4-bromo-butyloxy)-2-methyl-aceto phenone, which is collected at 162-l64/0.7 mm.

Example 12 The reaction of 5.7 of 4-(4-bronio-butyloxy)-3-methoxy-benzaldehyde with 6.5 g. of l-phenyl-piperazine in 20 ml. of ethanol, when carried out as described in Example 7 yields the 1-[4-(4-formyl-2-methoxy-phenyloxy)- butyl]-4-phenyl-piperazine of the formula n-r r--o-onronronrorn-N O CH;

CHg-CH /N CHr-CH;

which is converted into the dihydrochloride, M.P. 158 (with decomposition); yield: 2.8 g.

The starting material is prepared according to the procedure described in Example 11, by substituting 20.0 g. of vanilline for the 4-hydroxy-2-methyl-acetophenone; the desired 4-(4-bromo-butyloxy)-3-methoxy-benzaldehyde is collected at 164-1 66/ 0.2 mm.

Example 13 A mixture of 9.9 g. of 4-(4-brorno-butyloxy)-3-me- [All thoxy-n-butyrophenone, 9.7 g. of 1-phenyl-piperazine and OCH;

is dissolved in ethyl acetate and treated with a solution of hydrogen chloride in ethyl acetate; the resulting di- 14 hydrochloride salt is filtered off and recrystallized twice from ethanol, M.P. 188l90 (with decomposition); yield: 8.2 g.

The starting material is prepared as follows: A solution of 15.0 g. of 4-hydroxy-3-methoxy-n-butyrophenone in 50 m1. of ethanol'is added to 3.0 g. of sodium hydroxide in 40 ml. of ethanol while stirring, and the resulting mixture is treated with 22.0 g. of 1,4-dibromobutane in 25 ml. of ethanol. The reaction mixture is refluxed for 3% hours while stirring; the pH is about 6. After cooling and filtering, the solution is evaporated under reduced pressure. The residue is taken up in diethyl ether, the organic solution is washed with water and a dilute aqueous solution of sodium hydroxide, dried and concentrated. The desired 4-(4-bromo-butyloxy)-3-methoxy-n-butyropheone is isolated by distilling the residue and recovered at 180-190/0.2 mm.; yield: 13.0 g.

Example 14 A mixture of 7.18 g. of 4-(4-bromo-butylmercapto)- acetophenone and 8.1 g. of l-phenyl-piperazine in ml. of ethanol is refluxed for 18 hours. After cooling, the reaction mixture is filtered, the solid material is washed with ethyl acetate, and the combined organic solutions are concentrated under reduced pressure. The residue is dissolved in ethyl acetate; the organic solution is washed with Water, dried and concentrated under reduced pressure to yield 8.5 g. of 1-[4-(4-acetyl-phenylrnercapto)- butyl]-4-phenyl-piperazine of the formula which is converted into its dihydrochloride by dissolving the free base in ethyl acetate and treating it with a solution of hydrogen chloride in ethyl acetate. It is recrystallized twice from a mixture of methanol and ethyl acetate and melts at 186-190"; yield: 6.1 g.

The starting materials used in the above procedure is prepared as follows: A soultion of 22.0 g. of thiophenol in 100 ml. of ethanol is added to 8.0 g. sodium hydroxide in 100 ml. of ethanol, followed by a solution of 60.0 g. of 1,4-dibromobutane in ml. of ethanol. The reaction mixture is refluxed for one hour, then allowed to stand overnight at room temperature, filtered and concentrated. The residue is dissolved in diethyl ether; the organic solution is washed with 2 N aqueous sodium hydroxide and Water, dried and concentrated. The residue is distilled and the desired 4-bromo-butylmercaptobenzene is collected at 120/ 1.0 mm.

To a cold (0-10") suspension of 16.0 g. of anhydrous aluminum chloride in ml. of chloroform, is added 10.2 g. of acetyl chloride; while keeping the temperature at 1-5, a total of 24.5 g. of 4-bromo-butylmercaptobenzene is added slowly. The reaction mixture is allowed to warm to room temperature and is then stirred for thirty minutes and poured onto ice. The chloroform layer is separated, washed with water, dried and concentrated. The desired 4-(4-bromo-butylrnercapto) -acetophenone is obtained by distilling the residue and collected at l/0.5 mm.; yield: 15.0 g.

Example 15 A mixture of 6.9 g. of 4-(4-bromobutyloxy)-3-methoxyacetophenone and 8.8 g. of l-(2-methoxy-phenyl)-piper- CHg-CHZ GE -CH azine in 30 ml. of ethanol is refluxed for 24 hours and is worked up as described in Example 7 to yield the 1-[4- 15 16 (4-acetyl-2-methoxy-phenyloxy) butyl] 4 (2-methoxy- 4-(4-bromo-butyloxy)-3-ethoxy-acetophenone with 1-(2- phenyl)-piperazine of the formula methoxy-phenyl)-piperazine; and

OH2OH2 v H3CC O- H,CH;CH -H N Is II O CH2CH2 which is converted into its dihydrochloride, M.P. 200 1 [4 (2 methoxy 4 propionyl-phenyloxy)-butyl]- (with decomposition) after two recrystallizations from 4 (2 methoxy-phenyl)piperazine, which is characterethanol. ized as the hydrochloride salt and prepared by reacting Other compounds prepared according to the above 4 (4 bromo butyloxy) 3 methoxy propiophenone illustrated procedure by selecting the appropriate starting and I-(Z-methoxy-phenyl)-piperaziue.

materials are, for example, E l 16 1 [2-(4-acetyl-2-methoxy phenyloxy) ethyl] 4 (2- xamp e methoxyphenyl) -piperazine, the dihydrochloride of A mixture of 18.0 g. of l-[4-(4-acetyl-2-methoxywhich melts at 188 (with decomposition), and which is phenyloxy)-butyl]-4-phenyl piperazine dihydrochloride prepared by reacting 4-(2-chloroethyloxy)-3-methoxyand 350 ml. of water is stirred. After five minutes, the acetophenone with l-(2-rnethoxy-phenyl)-piperazine; solid material is filtered off; i represents the l-[3-(4-acetyl-2-methoxyphenyloxy) propyl] 4 (2- acetyl 2 methoxy phenyloxy) butyl] 4 phenylmethoxy phenyl) piperazine, the dihydrochloride of 90 pipcra zine monohydrochloride monohydrate, MI. 95- which melts at 222-225" (with decomposition), and 98; yield: 15.0 g. The dried monohydrochloride monowhich is prepared by reacting 4-(3-bromo-propyloxy)-3- 'hydrate is dissolved in 50 ml. of ethanol by heating; the methoxy-acctophenone with I-(Z-methoxy-phenyl)-pipersolution is diluted with 50 ml. Of ethyl acetate, Whereazine; upon the anhydrous 1-[4-(4-acetyl-2-methoxy-phenyloxy)- 1-[5-(4-acetyl-2-methoxy phenyloxy) pentyl] 4 (2- butyl] -4-phenyl-piperazine monohydrochloride of the 1 methoxy phenyl) piperazine, the dihydrochloride of formula which melts at 178-181" (with decomposition), and crystallizes, M.P. 153-154". A solution of 0.76 g. of which is prepared by reacting 4-(5-bromo-pentyloxy)-3- 1 [4 (4 acetyl 2 methoxy phenyl) butyl] 4- methoxy-acetophenone with l-(2-methoxy-phenyl)-piperphenyl-piper-azine, which is obtained from the dihydroazine;

1- 4- 2 acetyl phenyloxy) -butyl] 4 2 methoxy-phenyl) piperazine, the dihydrochloride of which 3.5 N solution of hydrogen chloride in ethyl acetate and melts at 198-200 (with decomposition), and which is diluted With diethyl ether, yields 0.6 g. of l-[4-(4-acetyl chloride by treatment with a base and melts at 74-76", in 2 ml. of ethanol, when treated with 0.53 ml. of a prepared by reacting 2-(4-bromo-butyloxy)-acetophenone 2-m th0xy phenyloxy) butyl] 4 phenyl piperazine 1 with 1 (2-methoxy-phenyD-piperazine; 40 monohydfochlol'ide, M-

1 [4 (3 acetyl phenyloxy) butyl] 4 (2 meth- The picrate of 1-[4-(4-acetyl-2-methoxy-phenyloxy)- oxy-phenyl) -piperazine, the dihydrochloride of which butyl]- -p enyl-piperazine is prepared by reacting the melts at 189-192" (with decomposition), and which is above free compound with picric acid in the presence prepared by reacting 3-(4-bromo butyloxy)-acetophenone f ethanol. with 1-(2-methoxy-phenyl)-piperazine; Example 17 1 acetyl Phehyioxy) hiiiyi] 4 (2 hieih' A mixture of 5.95 g. of 4-(4-acetyl-2-methoxy-phenyly-p y -p P the dihyqwchloride of w h 0xy)-butyl-amine and 5.45 g. of N,N-di-(2-chloroethyl)- melts at 216-220 (Wiih decomposition) and which is N-phenyl-amine in ml. of methanol is refluxed in the pr'epared b ti 4 (4-brqmo-butyloxy)-acet phen I resence of an excess of potassium carbonate for fifteen With l-( q y-p )P 0 hours While stirring. 'The solid material is filtered off, 1 cmnamoyi 2 meihoxy) hhiyi] 4 the filtrate is concentrated under reduced pressure, and

meihoxy'phehyi)lgipeihziheithe dihifiiiochioiide of w h the residue, representing the 1-[4-(4-acetyl-2-methoxymelts at 178-182 (with decomposition), and which is phenyloxy) butyu 4 phenyl piperazine is treated with a P p reacting 4 (4 h hiiiyioxy) 3 concentrated solution of hydrogen chloride in ethyl acetate thoxy -benzalacetophenone with 1-(2-methoxy-phenyD-pito yield the 1 [4 (4 acetyl z methoxy phenyloxy) buty1]; perazlne; 4-phenyl-piperazine dihydrochloride, M.P. 205 with de-.

1 acetyl 2 chioro P Y biiiyii' composition) after recrystallization from ethano l. 4 y-p y )-P P the y The starting material used in the above procedure is. ride of Which mel at (Wltil decomposition) and prepared as follows: A mixture of 30.8 g. of 4-(4-bromowhich is P P y {eacimg 4(4'hioiho'hiiiyihx3fi'3 0 butyloxy)-3-methoxy acetophenone and 22.0 g. of pochloro-acctop en w l-P P tassiurn phthalimide in 50 ml. of N,N-dimethylformamide aZlIle; is refluxed for two hours in the presence of a few crys- 1 acetylf 2 q y Phehyioxy) hhiyii tals of potassium iodide as a catalyst. The warm soluy phenyl) P P f the iiiohiihydiochio tion is poured onto crushed ice; the organic material is ride of which melts at 172-174 and which is prepared 5 extracted with chloroform, and the extract is washed y reacting 'bromohiiiyioxy) 3 hieihoxy' with a 1 N aqueous solution of potassium hydroxide,,0.5 acetophenone Wlt -p )P N aqueous hydrochloric acid and water. After drying 1 4 (4 t 1 2 methoxy: henyloxy) bu y lover sodium sulfate, the organic solution is concentrated 4 chiofo p P P the mohohydio to dryness under reduced pressure. The residue is treated chloride of which meiis at 160462: and which is with 200 ml. of methanol containing 20 ml. of hydrazine pared y reacting y Y hydrate 99-100% and refluxed for two hours. The

acc op W -p y )-P P solution is cooled, acidified with concentrated hydrochloric 1 [4 (4 acetyl 2 ethoxy phenyloxy) butyllacid and again refluxed thirtyminutes. After filtration, 4- (2-methoxy-phenyl)-piperazine, which is characterit is taken to dryness under reduced pressure, and the ized as t e hydrochloride salt and prepared by reacting residue is dissolved in a minimum amount of water. The.

the above procedure is prepared by heating a mixture of aniline and ethylene oxide in a sealed tube and converting in the resulting N,N-di-(2-hydr-oxyethyl)-N-phenylamine, the hydroxyl groups into chloro by treatment with thionyl chloride.

Example 18 A mixture of 12.1 g. of N-[4-(4-acetyl-2-methoxyphenyloxy)-butyl]-N,N-di-(2-chloroethyl)-amine and 3.1 g. of aniline in 50 ml. of methanol is refluxed in the presence of an excess of sodium carbonate for several hours while stirring. The solid material is filtered off, the filtrate is evaporated to dryness, and the residue,

18 1 [4 (4-acetyI-Z-methoxy-phenyloxy)-butyl] -4-'phenylpiperazine, is converted into its dihydrochloride, M.P. 205 (with decomposition).

The starting material used in the above procedure is prepared as follows: A mixture of 30.6 g. of N-phenylethylenediamine and 7.5 g. of 444-acetyl-2-methoxyphenyloxy)-butyl bromide in 150 ml. of ethanol is refluxed for 24 hours. After cooling and filtering, the solution is concentrated under reduced pressure, the residue is taken up in aqueous sodium hydroxide and extracted with benzene. concentrated under reduced pressure to yield the desired N [4- (4-acetyl-Z-rnethoxyphenyloxy)-butyl]-N-phenylethylenediamine, which is used in the next step without further purification.

Example The following compounds are prepared according to the previously-described procedure by selecting the appropriate starting materialsr Acyl-phenyl-X-lower alkyl halide N-Monocyclic aryl diaza- N-(Acyl-phenyl-X-lower alkyl)-N-monocyclic cycloalkane aryl-diaza-cycloalkane v 4-(4-bromo-butyloxy)-3meth0xy-acetophenone 4-(3-chloro-pr0pyloxy)-acetophenone 4-(2-ch1oro-ethyloxy)-propiophenone 4- (Z-chloro-ethyloxy)-3-methyl-acetophenone 4-(2-chloroethyl0xy)-3-methoxy-acetophenone 4-(4-bromo-butyloxy)-3-methoxy-acetophenone.

4-chloro-4'-(Z-chloroethyloxy)-benzophenone 4-(2-chlor0-ethyloxy)-4-methyl-benzophenone 4-(fi-bromo-pentyloxy)-3-chlor0-acetophenone..

2-(2-n1ethoxynicotinoyl-phenyloxy)-ethyl 1-(3 -meth 0xyphenyl)- piperazine.

1- (2-bromo-pheny1)- piperazine.

l-phenyl-piperazine 1- (2-pyridyl) -piperazine l l-phenyl-l,4'diaza-cycl0- heptane. 1-phenyl-2-rnethyl- 1-(4-methoxy-phenyD-piperazme.

l-(3-trifiuoro-methylphenyD-piperazine.

1-[4-(4acety1-2-methoxyphenyloxy)-butyl]-4-(3- methoxy-phenyl)-piperazine. 1-[3-(4-acetyl-phenyloxy)-propyl]-4-(2-bromophenyD-piperazine. i-phenyl-l-[2'(4-propionyl-phenyloxy)-ethyl-] piperazme. 1-[2-(t-acetyl-Z-methyl-phenyloxy)-ethyl]-4-(2- pyr1dyl)-piperazine. 1-[2-(4-acetyl-2-metboxy-phenyloxy)-ethyl]-4 phenyl-l,4-diaza-cycloheptane. 1-[4-(4-acetyl-2-methoxy-phenyloxy)-butyl]-3- piperazir e. methyl-4-pheuyl-piperazine. 1-phenyl-p1perazme 1 {2-[4-(4-chloro-benzoyl) -phenyloxy]-ethyl} -)-4 phenyl-piperazine.

chloride. piperazine. nicotinoyl phenyloxy)-ethyl1-piperazine. 4-(2-ch1oro'ethyl0xy)-3-methoxy'acetophenone l-phenyl-l,S-diaza-cyclo- 1-[2-(4-acetyl-2methcity-phenyloxy)-ethyl]-5- octane. phenyl-l,5-diaza-cyclo-octane. 4-(2-chloro-ethyl-mercapto)-acetophenone 1-(3 -rnethyl-phenyl)- 1-[2-(4-acetyl-phenyl-mercapto)-ethyl]1-(3- piperazme. methyl-phenyl)-piperazine. 4P(4-bromo-butyl-mercapto)-3-methoxyl-(2 -methoxy-phenyl)- 1-[4-(4-acetyl-2-methoxy-phenyl-mercapto)- acetophenone. plperazme. buty11-4-(2-meth0xy-phenyl)-piperazine.

representing the 1-[4-(4-acetyl-Z-methoxy-phenyloxy)- butyl]-4-phenyl-piperazine, is converted into its dihydrochloride, M.P. 205 (with decomposition) as described before.

The starting material used in the above procedure is prepared as follows: A mixture of 13.0 g. of 4-(4-acetyl- Z-methoxy-phenyloxy) butyl-amine and 4.5 g. of ethylene oxide is heated in a sealed tube at 90150 for several *hours. The reaction product is extracted with ethanol, and the organic solution is carefully concentrated under reduced pressure to yield the N-[4-(4-acetyl-2-methoxyphenyloxy) 'butyl] N,N di-(2-hydroxy-ethyl)amine, which is used without further purification.

To a suspension of 12.5 g. of powdered phosphorus pentach-loride in ml. of dry chloroform is added 17.1 g. of N-[4-(4-acetyl-2-methoxy-phenyloxy)-butyl]-N,N-di- (2hydroxyethyl)-amine while cooling. After refluxing for one hour, the resulting solution is poured onto ice, the chloroform :layer is separated, dried and concentrated under reduced pressure to yield the N-[4.(4-acetyl-2- methoxy phenyloxy) butyl] N,Ndi-(2-chloroethyl)- amine, which is used without further purification.

Example 19 A mixture of 11.2 g. of N-[4-(4acetyl-2-methoxyphenyloxy) butyl] N'-phenyl-ethylenediamine and 5.9 g. of ethylene bromide in 70 ml. of n-butanol containing a trace of water is refluxed for seventeen hours. After concentrating under reduced pressure, the residue is dissolved in diethyl ether, filtered, washed twice with water, dried and evaporated. The residue, representing the desired Example 21 Pharmaceutical compositions containing a compound of this invention are generally prepared according to methods used in the art of manufacturing pharmaceutical compositions, essentially by combining specified proportions of the pharmacologically active ingredient with a pharmaceutically acceptable organic or inorganic carrier. Usually, the compositions of this invention are made up to have from about 1 percent to about 50 percent by weight of the pharmacologically active ingredient in the composition. .In compositions for oral use (e.g. tablets, capsules and the like), the percentage by weight is from about 5 percent to at most 50 percent of the pharmacologically active ingredient. In compositions prepared for injection (esg. solutions and the like), the percentage by weight is from about 1 percent to about 20 percent of the active ingredient.

In preparing pharmaceutically acceptable dosage unit forms, any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions, suspensions and the :like. In addition to the pharmacologically active component, there are present additional substances commonly employed in the art of manufacturing pharmaceutically acceptable dosage unit compositions. These may include excipients, binders, fillers, lubricants, solvents, stabilizers, wetting agents, emulsifiers, buffers, and/or other pharmaceutically acceptable excipients, such as those mentioned previously.

Tablets, each containing 0.05 g. of 1-[4-(4-acetyl-2- The organic extract is dried and 19 methoxy-phenyloxy) -butyl] -4-phenyl-piperazine dihydrochloride, are prepared as follows (for 500,000 tablets):

Ingredients: G.

1 [4 (4 acetyl 2 methoxy phenyloxy) butyl] 4 phenyl piperazine dihydrochloride 25,0000 Lactose, spray dried 106,845.0 Corn starch 3,850.0 Corn starch (for paste) 2,860.0 Confectioners sugar 10,000.0 Stearic acid 1,445.0

Purified water, q.s. Alcohol, anhydrous 3A, q.s.

The 1 [4 (4 acetyl 2 methoxy phenyloxy) butyl]-4-phenyl-piperazine dihydrochloride is mixed with an equal portion of lactose; the mixture is passed through a No. 16 screen on a Fitzmill at medium speed and placed into a mixer. The remainder of the lactose, the 3,850.0 g. of corn starch, the confectioners sugar and the stearic acid are added, and the powder is mixed for twenty minutes. The 2,860.0 g. of corn starch is suspended in cold water and a paste is formed by diluting the mixture with 14,000 ml. of boiling water. The paste is then added to the dry powder mixture to form the granulate; granulation is completed by adding 1,000 ml. of a lzl-mixture of the 3A alcohol and water. The wet mass is passed through a No. 5 screen on the Fitzmill at low speed, dried on trays at about 43 and then broken on a No. 12 screen. The granulate is compressed into tablets weighing 0.3 g., using inch dies and standard concave punches.

Tablets, each containing 0.05 g. of 1-[4-(4-acetyl-2- methoxy phenyloxy) butyl] 4 phenyl piperazine hydrochloride, are prepared as follows (for 100,000

Purified water, q.s. Alcohol, anhydrous 3A, q.s.

The tablets are prepared according to the above described procedure. 7

Capsules, each containing 0.03 g. of 1-[4-(4-acetyl- 2 methoxy phenyloxy) butyl] 4 phenyl piperazine dihydrochloride, are prepared as follows (for 40,000 capsules):

Ingredients: G.

1 [4 (4 acetyl 2 methoxy phenyloxy) butyl] 4 phenyl piperazine dihydrochloride 1,200.0

Corn starch 700.0

Magnesium stearate 105.0

Lactose 11,9950

All ingredients are thoroughly mixed; the mixture is passed through a No. 30 screen, again mixed for an additional thirty minutes and then filled on an encapsulating machine into No. 2 clear, hard gelatine capsules, each containing 0.35 g. of material.

Capsules, each containing 0.03 g. of 1-[4-(4-acetyl-2- methoxy phenyloxy) butyl] 4 phenyl piperazine hydrochloride, are prepared as follows (for 100,000

capsules):

Ingredients: G.

1 [4 (4 acetyl 2 methoxy phenyloxy) butyl] 4 phenyl piperazine hydrochloride 3,000.0 Corn starch 1,750.0

Magnesium stearate Lactose The capsules are prepared according to the procedure described above.

Tablets, each containing 0.025 g. of 1-[4-(4-acetyl-2- methoxy-phenyloxy) -butyl] -4-phenyl-piperazine dihydrochloride, are prepared as follows (for 1,000 tablets):

The 1 [4 (4 acetyl 2 methoxy-phenyloxy) butyl]- 4-phenyl-piperazine dihydrochloride is passed through' a No. 30 screen, mixed with the tragacanth and lactose in a mixing machine and granulated with water. granules are dried at 25, passed through a No. 16 screen and mixed with the talcum, corn starch, stearic acid and magnesium stearate. The mix is compressed into tablets each weighing 0.15 g., using inch standard concave punches.

A solution for injection, containing per ml. 0.02 g. of 1 [4 (4 acetyl 2 methoxy-phenyloxy) butyl] 4- phenyl-piperazine dihydrochloride, is prepared as follows (for 1,000 ml.):

Ingredients:

1 [4 (4 acetyl 2 methoxy phenyloxy) butyl] 4 phenyl piperazine dihydrochloride g 20.00 Sodium chloride g 7.07 Water for injection, q.s. ml 1000.00

The 1- [4- (4-acetyl-2-methoxy-phenyloxy) -butyl] -4-phenyl-piperazine dihydrochloride is dissolved in 950 ml. of water for injection, the solution is heated to 40, and the sodium chloride is added. The solution is cooled to 25, and the volume is brought to 1000.00 ml. by adding the necessary amount of water. Throughout the procedure asceptic techniques are used, and the solution is filtered through a sterile filter into a 2,000 ml. flask, and 2.2 ml. 0 fthe solution is filled into 2 ml. amber ampules which are sealed and inspected.

A solution for injection, containing 0.025 g./ml. of 1 [4 (4 acetyl 2 methoxy phenyloxy) butyl] 4- phenyl-piperazinehydrochloride, is prepared as follows (for 5,000 ml.):

Ingredients 1 1 [4 (4 acetyl 2 methoxy phenyloxy) butyl] 4 phenyl piperazine dihydrochloride g 125.00 Sodium chloride g 35.35. Water for injection, q.s. ml 5000.00

The solution is prepared as described above.

Capsules, each containing 0.03 g. of 1-[4-(4-acetyl-2- methoxy phenyloxy) butyl] 4-(2-methoxy-phenyl)- piperazine dihydrochloride, are prepared as follows (for 20,000 capsules):

Ingredients: G.

1 [4 (4 acetyl 2-methoxy-phenyloxy)- butyl] 4 (2 methoxy-phenyD-piperazine dihydrochloride 600.0

Corn starch 350.0

Magnesium ste-arate 52.5

Lactose 5997.5

The capsules are prepared as described above.

Tablets, each containing 0.03 g. of 1-[4-(4-acetyl-2- methoxy phenyloxy) butyl] 4-(2-rnethoxy-phenyl) The 21 piperazine dihydrochloride, are prepared as follows (for 1,000,000 tablets):

Lactose, spray dried 233,690.0

Corn starch 7,700.0 Corn starch (for paste) 5,720.0 Confectioners sugar 20,0000 Stearic acid 2,890.0

Purified water, q.s. Alcohol, anhydrous 3A, q.s.

The tablets are prepared as described above.

Example 22 A solution of 6.1 g. of 4-(4-bromo-butoxy)-3=methoxyacetophenone and 8.9 g. of l-(2,5-dimethoxy-pheny1) piperazine in 40 ml. of ethanol is refluxed for 20 hours. The reaction mixture is evaporated to dryness and the residue partitioned between diethyl ether and water. The ether solution is washed twice with water and after drying over anhydrous sodium sulfate it is evaporated to dryness. The residue is dissolved in ethyl acetate and the solution made strongly acidic by the addition of a solution of hydrogen chloride in ethyl acetate. The solid formed is filtered off and after two recrystallizations from methanol there are obtained 4.3 g. of l-[4-(4-acetyl-2- methoxy phenyloxy) n butyl] 4-(2,5-dimethoxyphenyl)-piperazine dihydrochloride of the formula 0 CE; 0 CH melting at 206 with decomposition.

Example 23 A solution of 5.8 g. of 4 (3 bromo-propoxy)-3- methoxy-acetophenone and 8.9 g. of 1-(2,4-dimethoxyphenyl) -piperazine in 40 ml. of ethanol is refluxed for 18 hours. The reaction mixture is evaporated to dryness and the residue partitioned between diethyl ether and water. The ether solution is Washed twice with water and after drying over anhydrous sodium sulfate it is evaporated to dryness. The residue is dissolved in ethyl acetate and the solution made strongly acidic by the addition of a solution of hydrogen chloride in ethyl acetate. The crude dihydrochloride formed is filtered off and converted into the monohydrochloride on treatment with a small volume of water. After one recrystallization from ethanol there are obtained 4.0 g. of 1-[3-(4-acetyl- 2 methoxy phenyloxy) n-propyl]-4-(2,4-dimethoxyphenyl)-piperazine monohydrochlon'de of the formula melting at 18l183 Example 24 GET-C O O(CH;);N N- -2HCl 0 CH 0 CH melting at 186l90.

Example 25 A solution of 4.7 g. of 4'-(4-bromo-butoxy)-3-methoxy-propiophenone and 5.8 g. of l-(2-methoxy-phenyl)- piperazine in 20 ml. of ethanol is refluxed for 24 hours. After cooling, the reaction mixture is filtered and concentrated in vacuo. The residue is partitioned between diethyl ether and water and the ether solution is washed, dried and concentrated. The residue is taken up in ethyl acetate and the mixture is combined with a solution of hydrogen chloride in ethyl acetate. The precipitate formed is filtered off and recrystallized twice from ethanol to yield the 3'-methoxy-4-{4-[4-(2-methoxy-phenyl)-piperazino]-butoxy}-propiophenone dihydrochloride of the formula GH -OH CO 0 0 H 0 CH,

melting a-t 206208 with decomposition.

In the analogous manner the 3-methoxy-4'-[4-phenylpiperazino]-butoxy-propiophenone dihydrochloride of the formula C aCH2CO O OH;

M.P. l86188, is prepared.

The starting material can be obtained as follows: 4.8 g. of sodium hydroxide pellets are dissolved in 70 ml. of ethanol and a solution of 21.6 g. of 4-hydroxy-3-methoxypropiophenone in ml. of ethanol is added, followed by a solution of 39 g. of 1,4-dibromobutane in 40 ml. of ethanol. The reaction mixture is stirred at reflux for 2 hours. After standing at room temperature over night it is filtered and concentrated in vacuo. The residue is dissolved in 50 ml. of chloroform, the solution washed with N sodium hydroxide and water, dried and concentrated. The residue is distilled under reduced pressure and the fraction boiling at 174180 and 1 mm. Hg, representing the desired 4'-(4-bromo-butoxy) 3' methoxy-propiophenone, is collected.

Example 26 2.5 g. of 4-(4-bromo-butoxy)-3-methoxy-butyrophenone are reacted with 2.9 g. of l-(2-methoxy-phenyl)-piperazine in 10 ml. of ethanol according to the method given in Example 25. There is obtained the 3'-methoxy- 4 {4 [4 (2 methoxy-phenyl)-piperazino]-butoxy}- butyrophenone dihydrochloride of the formula CH CH2OH 0o- 00H, 00H;

melting at l96200 with decomposition.

The starting material is prepared by using 15 g. of 4'- hydroxy-3-methoxy-butyrophenone, dissolved in 40 ml. of ethanol, and reacting it with 3 g. of sodium hydroxide in 40 ml. of ethanol, followed by 22 g. of 1,4-dibromobutane in 25 ml. of ethanol and carrying out the reaction and isolation as in Example 25. The 4-(4-bromo-butoxy)-3-methoxy-butyrophenone boils at l90 and 0.2 mm. Hg.

Example 27 A solution of 4.6 g. of 3' chloro-4'-(4-bromo-but0xy)- acetophenone and 4.9 g. of l-phenyl-piperazine in 20 ml.

23 of ethanol is refluxed for 24 hours andworked up as described in Example 25. There is obtained the 3-chloro- 4'[4-(4-pl1enylpiperazino)-butoxy]-acetophenone dihydrochloride of the formula O-(CHah-N N -2HCI GHQ-C O- 01 melting at 202206.

Example 28 A solution of 4.7 g. of 4'-(4-bromo-butoxy)-3'-ethoxyacetophenone and 4.9 g. of l-phenyl-piperazine or 6.0 g. of 1-(Z-methoxy-phenyl)-piperazine in 20 ml. of ethanol is refluxed for 24 hours and worked up as described in Example 25. There are obtained the 3'-ethoxy-4-[4-(4- phenyl piperazino)-butoxy]-acetophenone dihydrochloride of the formula o oH2 .,-N N --2nc1 CH3C O Q2115 melting at 171174, and the 3'-ethoxy-4-{4-[4-(2- methoxy phenyl) piperazino] butoxy} acetophenone dihydrochloride of the formula N W L OH3CO OCzHs melting at 198-200", respectively.

The 4' (4 bromo butoxy)-3-ethoxy-acetophenone is prepared by reacting a solution of 15.4 g. of 3'-ethoxy- 4'-hydroxy-acetophenone in 50 ml. of ethanol with 3.5 g. of sodium hydroxide in 50 ml. of ethanol and 27.5 g. of 1,4-dibromobutane in 25 ml. of ethanol, refluxing the reaction mixture for 2% hours and working it up as described in Example 25. The 4-(4-bromo-butoxy)-3- ethoxy-acetophenone boils at 180 and 0.7 mm. Hg.

Example 29 A solution of 4.3 g. of 4-(4-bromo-butoxy)-3'-methylacetophenone and 5.8 g. of 1-(Z-methoxy-phenyl)-piperazine or 4.9 g. of l-phenyl-piperazine in 20 ml. of ethanol is refluxed for 24 hours and worked up as described in Example 25. There are obtained the 3'-methyl-4'- {4 [4 (2 methoxy phenyl) piperazino] butoxy}- acetophenone dihydrochloride, of the formula melting at 214-216 with decomposition, and the 3'-methyl-4- [4-(4-phenyl-piperazino)-butoxy] -acetophenone dihydrochloride of the formula ocH, ,N N -arm1 Example 30 A solution of 5.7 g. of 3'-methoxy-4-[4-(4-phenylpiperazino) butoxy] acetophenone and 4.4 g. of nbutylamine in 20 ml. of ethanol is refluxed for 24 hours. The reaction mixture is evaporated in vacuo to dryness. The residue is dissolved in ethyl acetate, the solution washed with water, dried and concentrated. The residue is again dissolved in ethyl acetate and the solution combined with a solution of hydrogen chloride in ethyl acetate. The precipitate formed is filtered off and recrystallized from a mixture of chloroform and hexane. There is obtained the 1-{4-[4-(1-butylimino-ethyl)-2 methoxy phenoxy] butyl}-4-phenyl-piperazine trihydrochloride of the formula O (CH2)4N N .s11c1 C x- O CH;

NC4Hfl(u) melting at 147 with decomposition.

Example 31 By using 4.0 g. of 3-methoxy-4{3-[4-(2-methoxyphenyl)-piperazino]-propoxy}-acetophenone and 2.9 g. of n-butylamine in 20 ml. of ethanol according to the method described in Example 30 there is obtained the 1-{3-[4-(1- butylimino-ethyl)-2-methoxy-phenoxy] propyl} 4 (2.

methoxy-phenyl)-piperazine trihydrochloride of the formula O(OH2)3N N- -3HC1 0113-0 --OCH OCH;

melting at with decomposition.

Example 32 A solution of 5.7 g. of 3'-methoxy-4'[4-(4-phenyl piperazino)-butoxy]-acetophenone, 2.1 g. of hydroxylamine hydrochloride and 4.5 ml. of pyridine in 50 ml. of

ethanol is refluxed for 24 hours. On cooling the crystallized product is filtered off and recrystallized twice from methanol to yield the oxime of 3'-methoxy-4' [4-(4-phenylpiperazino)-butoxy]-acetophenone monohydrochloride of melting at 188490".

Example 33 By reacting 4.0 g. of 3'-methoxy-4'-{3-[4-(2-methoxyphenyl)-piperazino]-propoxy}-acetophenone, 1.4 g. of hydroxylamine hydrochloride, 3 ml. of pyridine and 40 ml. of ethanol according to the method given in Example 32, the oxime of 3-methoxy-4'-{3-[4-(2-methoxy-phenyl)- piperazino]-propoxy}- acetophenone monohydrochloride,

of the formula 2)sN N- -HCl CH -C 0 CH3 0 CH;

N OH

is obtained. It melts after recrystallization from ethanol at ZOO-201.

Example 34 6.0 g. of 3'-methoxy-4'-{3-[4-(2,4-dimethoxy-phenyl)- piperazino]-propoxy}-acetophenone are reacted with 1.95 g. of hydroxylamine hydrochloride and 4.2 ml. of pyridine in 55 ml. of ethanol according to the procedure of Example 32, the oxime of 3'-methoxy-4-{3-[4-(2,4-di- 25 methoxy-phenyl) -piperazino] -propoxy}-acetophenone hydrochlon'de of the formula OCH OCH;

is obtained. It melts after recrystallization from ethanol at l98200.

Example 35 6.2 g. of the oxime of 3'methoxy-4-{3-[4-(2-methoxyphenyl)-piperazino]-propoxy}-acetophenone hydrochloride are treated with 50 ml. of 2 N sodium hydroxide, the base is extracted with chloroform, the solution is washed with water, dried and concentrated. The crystalline base melts at 144145.

4.1 g. thereof are dissolved in 82 m1. of dimethyl formamide and 8 m1. of toluene and 0.5 g. of a 53% suspension of sodium hydride in mineral oil are added. After stirring the mixture for 1 hour at 25, 1.42 g. of methyl iodide are added. The reaction mixture is stirred at 25 for 4 hours, filtered and the filtrate concentrated in vacuo. The residue is dissolved in ethyl acetate, the solution is Washed with water and dried. On addition of a solution of hydrogen chloride in ethyl acetate a precipitate is formed, it is filtered off and recrystallized twice from isopropanol. There is obtained the O-methylether of the oxime of 3'-methoxy-4'-{3- [4-(2-methoxy-phenyl)-piperazino]-propoxy}-acetophenone dihydrochloride of the formula NOOH -oon,

melting at 180-l82 with decomposition.

Example 36 N-NHz OCH melting at 91.

The dihydrochloride thereof is prepared from a solution of the base in ethyl acetate solution by adding a solution of hydrogen chloride in ethyl acetate and recrystallizing the precipitate formed from isopropanol, M.P. 257.

Example 37 After refluxing 2 g. of 3-methoxy-4-{3-[4-(2-methoxyphenyl)-piperazino]-propoxy}-acetophenone with 1.1 g. of semicarbazide hydrochloride, 1.6 ml. of pyridine and 5 ml. of water in 20 ml. of ethanol for 2 hours, the solids formed are separated after cooling by filtration and are washed with ethanol and dried. They represent the monohydrochloride of the semicarbazone of 3'-methoxy- 4' {3 [4-(Z-methoxy-phenyl)-piperazino] propoxy}- acetophenone having the formula O(GH2)3N N-H o1 GH -o 0 OH; 011

N-NHC ONE:

and melting at 248250.

Example 38 A mixture consisting of 5.7 g. of 4-(3-bromo-propoxy)-3-methoxy-acetophenone, 3.8 g. of 1-(3-methoxyphenyl)-piperazine, 2.1 g. of anhydrous sodium carbonate and 30 ml. of ethanol is refluxed with stirring for 24 hours. The reaction mixture is concentrated and the residue partitioned between water and chloroform. The chloroform solution is dried and concentrated to a small volume. On addition of a solution of hydrogen chloride in ethyl acetate the 3-methoxy-4{3-[4-(3-methoxy-phenyl -piperazino] -propoxy}-acetophenone dihydrochloride of the formula OCH O s crystallizes and after two recrystallizations from ethanol it melts at 169-172 with decomposition.

Example 39 By using an equal amount of 1-(4-methoxy-phenyl)- piperazine in Example 38, and following the procedure given therein, the 3-methoxy-4-{3-[4-(4-methoxy-phenyl)-piperazino]-propoxy-}-acetophenone of the formula is obtained; it melts after recrystallization from ethanol at 198201.

CH CO O CH;

Example 40 CHg-CO- 0 011;; (50 11 is obtained; it melts at -177 with decomposition, after two recrystallizations from ethanol.

Example 41 By using 2.9 g. of 4'-(3-bromo-propoxy)-3'-methoxyacetophenone, 2.1 g. of 1-(2-methylthio-phenyl)-piperazine, 1.0 g. of anhydrous sodium carbonate and 15 ml. of ethanol and following the procedure given in Example 38 the 3'-methoxy-4'-{3-[4-(2-methylthio-phenyl)-piperazino]-propoxy}-acetophenone dihydrochloride of the formula eu o 0- 0011 gn,

27 is obtained; it melts at 181-183" after recrystallization from ethanol.

Example 42 A mixture consisting of 5.7 g. of 4'-(3-bromo-propoxy)-3'-methoxy-acetophenone, 3.3 g. of 1-(2-pyridyl)- piperazine, 2.1 g. of anhydrous sodium carbonate and 30 ml. of ethanol is refluxed with stirring for 20 hours and worked up as described in Example 25. There is obtained the 3'-methoxy-4'-{3-[4-(2-pyridyl)-pipe1 azino]- propoxy}-acetophenone dihydrochloride of the formula CHgCO OCH;

melting at 190 with decomposition after having recrystallized it from methanol.

Example 43 By using 2.9 g. of 4'-(3-bromo-propoxy)-3'-methoxyacetophenone, 1.6 g. of 1-(2-pyrimidinyl)-piperazine, 1.1 g. of anhydrous sodium carbonate and 30 ml. of ethanol, refluxing the mixture for 20 hours and working it up as described in Example 40, the 3'-methoxy-4-{3-[4-(2- pyrimidinyl)-piperazino] propoxy} acetophenone dihydrochloride of the formula CH, OCH

is obtained; it melts at 204-208 after recrystallization from methanol.

Example 44 CH CO OCH; OGHQ melting at 203-205 after recrystallization from ethanol.

What is claimed is: 1. A member selected from the group consisting of a compound of the formula in which Ac is the acyl radical of an organic carboxylic acid selected from the group consisting of lower alkane carboxylic acid, lower alkene carboxylic acid, benzene carboxylic acid, phenyl-lower alkane carboxylic acid, phenyllower alkene carboxylic acid, pyridine carboxylic acid, pyridyl-alkane carboxylic acid and pyridyl-alkene carboxylic acid, Ph is a member selected from the group consisting of phenylene, phenylene substituted by lower alkoxy, phenylene substituted by lower alkyl and phenylene substituted by halogen, X is a member selected from the group consisting of oxygen and sulfur, Alk is lower alkylene having two to seven carbon atoms and separat ing the group X from the nitrogen atom by two to five carbon atoms, each of Alk and Alk is alkylene having from two to seven carbon atoms and separating the two nitrogen atoms by two to three carbon atoms, and Ar is a member selected from the group consisting of (1) phenyl,

(2) phenyl at most disubstituted by a member selected from the group consisting of lower alkyl, lower alkoxy and halogen, (3) pyridyl, (4) furyl and (5) thienyl, and

a lower alkylirnine, the oxime, an O-lower alkyloxime,

the hydrazone, the semicarbazone and the N-oxide there-.

3. 1-[3-(4-acetyl-2 methoxy-phenyloxy) propyl] 4- (2,4-dimethoxy-phenyl -piperazine monohydrochloride.

4. A member selected from the group consisting of a compound having the formula in which A stands for a member selected from the group consisting of lower alkanoyl, benzoyl, phenyllower alkanoyl, phenyl-lower alkenoyl and pyridoyl, each of the groups R R and R for a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halogeno, X for a member selected from the group consisting of oxygen and sulfur the letter In for an integer from two to six, and R for a member selected from the group consisting of hydrogen and methyl, a lower alkylimine, the oxime, O-lower alkyloximes, the hydrazone and semicarbazone thereof and acid addition salts of these compounds.

5. A member selected from the group consisting of a compound having the formula in which Ac stands for lower alkanoyl, each of R and R for a member selected from the group consisting of hydrogen, lower alkyl, lower alk-oxy and halogeno, R

for a member selected from the group consisting of hycompound having the formula shown in claim 3, in which Ac stands for acetyl, R for lower alkoxy, R for a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halogeno, R for hydrogen and the letter m for one of the integers from 2 to 4, a lower alkylimine thereof and acid addition salts of these compounds.

7. A member selected from the group consisting of 1-[4-(4-acetyl-2-rnethoxy-phenyloxy)-butyl] 4 phenylpiperazine and an acid addition salt thereof.

8. A member selected from the group consisting of 1-[4-(4-acetyl-2-methoXy-phenyloxy)-butyl] -4-(3 methyl-phenyl)-piperazine and an acid addition salt thereof.

9. A member selected from the group consisting of 1-{4- [4-(4-chloro-cinnamoyl) 2 methoxy phenyloxy]- butyl}-4-phenyl-piperazine and an acid addition salt thereof.

10. A member selected from the group consisting of 1-[4-(4-acetyl-phenyloxy)-butyl]-4-phenyl-piperazine and 14. A member selected from the group consisting of 1-[3-(4-acetyl-Z-methoxy-phenyloxy)-propyl] -4 (2 me-.

29 thoxy-phenyD-piperazine, and an acid addition salt thereof.

15. A member selected from the group consisting of 1-[3-(4-acetyI-Z-methoxy-phenyloxy)-propyl] 4-(2,4 dimethoxy-pheny1)-piperazine, and an acid addition salt thereof.

16. A member selected from the group consisting of 1-[4-(4-propionyl-2-methoxy-phenyloxy) butyl] 4 (2- methoxy-phenyl)-piperazine, and an acid addition salt thereof.

17. A member selected from the group consisting of the 'oxime of 1-[4-(4-acetyl-2-methoxy -phenyloxy) bultyl] -4-phenyl-piperazine and an acid addition salt thereof.

18. A member selected from the group consisting of the oxime of 1-[3-(4-aoetyl-2-methoxy-phenyloxy) -propy1]-4-(2,4-dimethoxy-phenyl) -piperazine and an acid addition salt thereof.

19. A member selected from the group consisting of the hydraz'one of 1-[3-(4-acety1-2-methoxy-pheny1oxy)- propyl]-4-(2-methoxy-phenyl) -piperazine and an acid addition salt thereof.

20. A member selected from the group consisting of 1- [3 4-acetyl-Z-methoxy-phenyloxy -propyl] (2 pyrimidinyl)-piperazine, and an acid addition salt thereof.

References Cited by the Examiner UNITED STATES PATENTS 3,038,901 6/1962 Hayao et al. 260268 3,067,202 12/1962 Patton et al. 260268 3,106,557 10/1963 Poppelsdorf et al. 260268 3,138,598 6/ 1964 Speranzo 260268 3,170,926 2/1965 Ash et al. 260268 ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

JAMES W. ADAMS, JR., Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non 3,277,094 October 4, 1966 Lincoln Harvey Werner It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 30, line 2, after "-propyl]" insert 4- o Signed and sealed this 22nd day of August 1967 L) Anmm EBEUPYV.SVFUUER Attesting Officer EIHYARD L BRENNER.

Commissioner of Patents 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 